New selective chemical reactions are essential components to advance biology and medicine. The most powerful and efficient chemical reactions commonly use catalysis to control reactivity and selectivity. The discovery of new catalyst concepts with broad utility beyond established reactivity can greatly impact biomedical research by providing unconventional and efficient access to compounds with biological activity. The long-term goal of our catalysis research is to develop new Lewis base-catalyzed transformations with direct application to the syntheses and investigation of bioactive molecules. Our development of N-heterocyclic carbenes (NHCs) as catalysts will continue to uncover new approaches and generate important new concepts of organocatalysis. Our central hypothesis is that new discoveries in the field of carbene catalysis will significantly advance chemical synthesis, bioorganic chemistry and medicine. The specific goals of this proposal are: (1) Develop new cooperative carbene catalysis processes. N-heterocyclic carbenes (Lewis bases) have been discovered to be compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acids, hydrogen bond donors or transition metal complexes with NHCs will provide new opportunities for chemical synthesis; (2) explore azolium-based activation for substitution reactions; (3) investigate carbene catalysis-driven total syntheses. While there has been an explosion of new NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed intramolecular Michael reaction as the key step in the synthesis of arnamial and related natural products. In addition, a trans-annular NHC-catalyzed lactone formation will be pursued as the main approach to synthesize repin, a potent cytotoxin. Our research in generating new reactivity using organocatalysis will establish new approaches for the efficient synthesis of molecules. This research will also provide important knowledge about nucleophile-catalyzed polarity reversal reactions and cooperative catalysis. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for medically relevant synthesis and thus further the mission of NIGMS.